510 FARMACIA, 2012, Vol.

60, 4

THE PREVALENCE OF POTENTIAL DRUG-

DRUG INTERACTIONS IN THE THERAPY OF
ROMANIAN COMMUNITY PHARMACY’S
PATIENTS
CAMELIA DENISA BUCSA*, IRINA CAZACU, ANDREEA MARIA
FARCAS, MARIUS BOJIȚĂ
Drug Information Research Center, Faculty of Pharmacy, University of
Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Romania
*corresponding author: cfarah@umfcluj.ro
Abstract
Drug-drug interactions (DDIs) are a concern for patients and providers, as
multiple medication use is becoming more common to manage complex diseases. However,
a high prevalence of potential drug-drug interactions (pDDIs) can lead to a higher
probability to develop an adverse drug reaction (ADR) or suboptimal therapeutic effects.
The objective of our study was to measure the frequency, nature and severity of the
potential DDIs in prescriptions from a Romanian community pharmacy. We analysed 308
prescriptions (all reimbursed prescriptions from one month) of 243 patients for the
detection of the pDDIs. Our study showed that potential drug-drug interactions are highly
prevalent (34.42% of prescriptions with at least one DDI) in patients’ therapy and the
modernization of prescribing and dispensing medicines is necessary.
Rezumat
În terapia modernă polimedicația este o necesitate în cazul pacienților cu mai
multe afecțiuni, dar aceasta poate determina o incidență crescută a interacțiunilor
medicamentoase și a reacțiilor adverse la medicamente sau reducerea efectului terapeutic
ale acestora. Obiectivul studiului de față a fost determinarea frecvenței, naturii și severității
interacțiunilor medicamentoase potențiale identificate în prescripțiile din farmacia
comunitară din România. Au fost analizate 308 rețete compensate provenite de la 243 de
pacienți dintr-o farmacie, pe parcursul unei luni. Rezultatele studiului arată o prevalență
ridicată a interacțiunilor medicamentoase potențiale în terapia pacienților, subliniindu-se
astfel nevoia existenței sistemelor computerizate de semnalare a interacțiunilor
medicamentoase, atât la nivelul prescrierii de către medic, cât și la nivelul eliberării
medicamentului de către farmacist.
Keywords: drug-drug interactions, adverse drug reactions, community pharmacy.

Introduction
Adverse drug reactions (ADRs) represent a major health issue
worldwide, as their consequences are often serious - accounting for up to
18% of hospital admissions and being the sixth leading cause of mortality
[1,11,15,16]. An observational study conducted in an internal medicine
ward in Romania showed that ADRs represent 6% of the total number of
admission causes. The same study showed that 25.9% of all validated ADRs
(detected at the admission or during hospitalization) are consequences of
drug-drug interactions (DDIs) [9].
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DDIs are an important cause of ADRs and may lead to an increased

risk of hospitalization (2.8% of hospital admissions) and higher healthcare
costs [12,18,19].
DDIs are a concern for patients and providers, as multiple
medication use is becoming more common to manage complex diseases.
Polypharmacy is the most important risk factor for DDIs [7,10]. The
prescription of more drugs for one patient is a common and necessary
practice for the patients, but physicians should keep in mind that the
incidence of potential DDIs approaches 40% for patients taking 5 drugs, and
exceeds 80% for patients taking 7 or more medications [10]. In addition to
polypharmacy, age is also a key risk factor for DDIs along with acute
medical condition, female sex, prescriptions from multiple physicians and
drugs with narrow therapeutic range [3,4,22].
Studies on the subject of potential DDIs (pDDIs) in out-patients
therapy were conducted in different countries, but to our knowledge, not in
Romania. Regarding the elderly, Björkman et al found in their study made
on 6 European countries pharmacies, 0.83 potential DDIs/person and 46%
of the patients had at least one potential DDI [5], while in Mexico the
percentage of elderly patients with at least one DDI was almost double
(80%)[8]. In Switzerland the percentage of potential DDIs in general
population prescriptions was 23% according to Dallenbach et al [7] and in
Dutch pharmacies was found that only 6% of the prescriptions presented at
least one potential DDI [6].
Because of the differences among the healthcare systems, results
from one country prevalence studies cannot be extrapolated to other
countries. Drugs that are approved to be marketed and reimbursed in some
countries, and also the prescribing policies, may be very different in others.
The aging of the population and the increasing complexity of the patients’
medication regimens, as well as the fragmented healthcare system in
Romania, with multiple prescribers for one patient and no electronic charts,
are important elements that might lead to DDIs [14,21].
The objective of our study was to measure the frequency, nature and
severity of the potential DDIs in prescriptions from a Romanian community
pharmacy.

Materials and Methods

The retrospective study was conducted on the one month (30 days)
period reimbursed prescriptions (January 2010) from a community
pharmacy from Romania.
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We analysed 308 prescriptions for 243 patients for pDDIs using

Thomson Micromedex program [13]. If a patient presented to the pharmacy
with more than one prescription, all prescriptions were analysed in order to
detect the pDDIs between drugs on different prescriptions, if the drugs were
meant to be taken in the same period of time.
We define a potential DDI as being a pair of drugs that interact in
such a manner that the effectiveness or toxicity of one or two drugs might
be altered.
Potential DDIs were classified according to Micromedex program as
contraindicated associations (the drugs are contraindicated for concurrent
use), major DDI (the interaction may be life-threatening and/or require
medical intervention to minimize or prevent serious adverse effects),
moderate DDI (the interaction may result in exacerbation of patients’
condition and/or require a modification in therapy) and minor (the
interaction would have limited clinical effects). The most severe category is
the contraindicated association.
Data including age, sex, medication, detected pDDIs and degree of
severity were analysed using descriptive statistics.

Results and Discussion

Patients’ characteristics and prescribed drugs
Two hundred and forty-three patients presented to a community
pharmacy in January 2010 with 308 reimbursed prescriptions issued by a
general practitioner or by the specialist. The number of medicines
prescribed was 931 (3.83 drugs/patient) out of which 913 were purchased
(18 drugs not taken by 15 patients): cardiovascular drugs represent the great
majority of prescribed drugs (64.03%). Patients’ characteristics and
prescribed drugs are presented in Table I.
Table I
Characteristics of the patients and prescribed drugs.
Characteristics
Age-years (n=243) Mean (95% CI) 60.78 (57.74-63.82)
Gender-no. (%) Male 99 (40.74)
(n=243) Female 144 (59.26)
Medicines prescribed (n=931) ATC* Cardiovascular system (C) 596 (64.03)
group-no. (%) Nervous system (N) 65 (6.99)
Alimentary tract and metabolism (A) 60 (6.43)
Antiinfectives for systemic use (J) 57 (6.13)
Musculoskeletal system (M) 54 (5.81)
Respiratory system (R) 50 (5.38)
Genitourinary system and sex hormones (G) 21 (2.26)
Blood and blood forming organs (B) 16 (1.73)
Other groups 11 (1.20)
*Anatomical Therapeutic Chemical (ATC) group [12] , CI-confidence interval
FARMACIA, 2012, Vol. 60, 4 513

Potential DDIs
In the 243 patients included in the study with 308 prescriptions, we
identified 252 pDDIs (1.04 pDDIs /patient). Our study confirmed our
supposition that pDDIs have a high prevalence in patients’ therapy, 117
(48.15%) patients being at risk of developing negative consequences of a
DDI (an ADR or the loss of the therapeutic effect). The numbers are lower
than the ones found in Mexico outpatients (80%) but higher than in a study
performed in hospitalized patients in Switzerland (30% at hospital entry)
[23] and higher than in geriatric outpatients from the Netherlands (25%)
[22]. Regarding the prevalence of prescriptions containing a pDDI, in our
study 106 (34.42%) of the total number of prescriptions contain at least one
pDDI. To this number we should also add the 29 cases of patients having a
second (or third) prescription and presenting pDDIs between drugs from
different prescriptions being administered in the same period of time (56
pDDIs). We should also mention that the total number of prescriptions (308)
includes the one-drug prescriptions as well. In Thai out-patients the
prevalence of prescriptions containing at least one pDDI was 20.06%, but in
Dutch community pharmacies it was found that only 6% of the prescriptions
presented at least one potential DDI [6].
As for the number of pDDIs per patient our result (1.04
pDDIs/patient) is comparable to the highest values from a study performed
on the elderly from six European countries. In the Republic of Ireland and
Germany the results were close to ours (1.05 and 1.04 respectively) but in
countries like Portugal and Northern Ireland (0.62 and 0.67 respectively) the
number of pDDIs per patient was significantly lower [5].
The majority of pDDIs were between the medicines on the same
prescription - 196 pDDIs (77.78%) in 106 prescriptions and in 29 patients
we found 56 pDDIs (22.22%) between drugs on different prescriptions but
to be taken during the same period of time. The association of angiotensin
converting enzyme (ACE) inhibitors with thiazide diuretics was the most
prevalent pDDI (found in 54 patients), followed by the combination beta-
adrenergic blockers and dihydropyridine calcium channel blockers (in 31
patients) and ACE inhibitors again combined with non-steroidal anti-
inflammatory drugs (NSAIDs) in 15 patients. These results can be explained
by the fact that the cardiovascular drugs constitute the great majority of the
prescribed drugs (64.03%), similar with another study results [17]. All these
three combinations are of “moderate” severity and could have led to
postural hypotension (first dose), hypotension and/or bradycardia and
decreased antihypertensive effects respectively. The most prevalent “major”
pDDIs were the associations of calcium channel blockers with statins (13
514 FARMACIA, 2012, Vol. 60, 4

patients) which may lead to myopathy or rabdomyolysis and Ginko biloba

extract combined with NSAIDs (in 5 patients), with an increased risk of
bleeding.
We did not found “contraindicated associations” and the number of
“major” pDDIs was 50 (19.84%); the majority of pDDIs were “moderate” -
192 (76.19%) and “minor” - 10 (3.97%) pDDIs. In Table II are listed the
most prevalent pDDIs and their severity category.
Table II
The most prevalent pDDIs
Drug combinations Number of Severity Potential effect of the DDI
potential DDIs
(n=252), (%)
ACE inhibitors + thiazide diuretics 54 (21.43) moderate May result in postural
hypotension (first dose)
Beta-adrenergic blockers + 31 (12.31) moderate May result in hypotension
dihydropyridine calcium channel and/or bradycardia
blockers
ACE inhibitors + NSAIDs 15 (5.95) moderate Decreased antihypertensive
effects
Calcium channel blockers + statins 13 (5.16) major Increased exposure to statins
and increased risk of
myopathy or rabdomyolysis
Beta-adrenergic blockers + NSAIDs 11 (4.36) moderate Decreased antihypertensive
effects
Beta-adrenergic blockers + digoxin 10 (3.97) moderate May result in digitalis toxicity
(nausea, vomiting,
arrhythmias) and/or AV block
Beta-adrenergic blockers + 8 (3.17) moderate May result in hypoglycaemia,
antidiabetic agents hyperglycaemia or
hypertension
Dihydropyridine calcium channel 7 (2.78) minor Increased risk of gastro-
blockers + NSAIDs intestinal haemorrhage
Thiazide diuretics + NSAIDs 6 (2.38) moderate Decreased antihypertensive
and diuretic effects
Beta-adrenergic blockers + alpha 6 (2.38) moderate May result in postural
blockers hypotension (first dose)
Ginko biloba extract + NSAIDs 5 (1.98) major Increased risk of bleeding
Other potential DDIs 86 (34.13)

In clinical practice certain associations can be prescribed often

because it is considered that the benefit outweighs the risk (eg. ACE
inhibitors + thiazide diuretics). In this cases careful monitoring and
counselling of the patients are necessary in order to avoid the occurrence of
adverse drug interactions.
We did not investigate if any of the pDDIs detected materialized in
negative clinical consequences, but it is important to remember that a high
prevalence of pDDIs leads to a higher probability to develop an ADR or
FARMACIA, 2012, Vol. 60, 4 515

suboptimal therapeutic effects, and further more, they can seriously affect
the patients’ safety and increase the healthcare costs.
Differences among the countries are likely to reflect different therapy
traditions as well as different policies regarding the use and implementation
of clinical guidelines. However, health professionals from countries like the
Netherlands and Portugal are being helped in their prescribing activity by
well-organized health systems, where different support strategies for risk
management are available (electronic prescription entry, computerized
medication records). Systematic screening for DDIs can be fastidious and
time-consuming in the rapidly growing field of therapeutics.
A limitation of our study is the fact that the prescriptions studied were
only the reimbursed ones and besides those, the patients might also have
been on other medications (non-reimbursed medications, “over the counter
drugs”). If to the considered medication, the patient would have taken a low
dose of aspirin for example, the number of pDDIs would be a lot greater.

Conclusions
A 2007 World Health Organization report referring to the cases of
drug-drug interactions from the Vigibase (the international ADR database)
stated that co-medication of contraindicated drugs is a longstanding
international problem [20].
Our study showed that potential drug-drug interactions are highly
prevalent in patients’ therapy. The use of modern computerized programs in
the prescription practice and in pharmacies is necessary in order to prevent
ADRs and other negative consequences of drug interactions. Further
research could look in to which of the pDDIs have clinical consequences.

Aknowledgements
This study is part of a POSDRU grant (88/1.5/S/56949).

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Manuscript received: December 16th 2010